Broad Spectrum of Upfront Therapies Available for Follicular Lymphoma

John M. Burke, MD

Patients with follicular lymphoma (FL) have a number of treatment options upfront, as well as in the second-line setting and beyond. This leaves physicians with important treatment decisions to make, and several factors should be considered to make the appropriate selection, including disease stage and tumor burden.

In the frontline, patients with early-stage disease with low tumor burden or who are asymptomatic can be managed with the watch-and-wait approach, but if patients are uncomfortable with this strategy, single-agent rituximab (Rituxan). For patients with more advanced disease and high tumor burden, the treatment options include chemoimmunotherapy regimens, such as rituximab- or obinutuzumab- (Gazyva) based therapies. The chemotherapy options include either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); or bendamustine.

The options in the relapsed/refractory setting similarly include chemoimmunotherapy regimens and targeted therapies, but the landscape was recently enriched with the addition of the FDA-approved EZH2 inhibitor tazemetostat (Tazverik) for the treatment of patients with relapsed/refractory FL whose tumors harbor EZH2 mutations and who have received at least 2 prior lines of systemic therapy, and the for treatment of adult patients with relapsed/refractory FL who have no satisfactory alternative treatment options.

In an interview with Targeted Oncology, John M. Burke, MD, associate chair of the Hematology Research Program for US Oncology and medical oncologist and hematologist at Rocky Mountain Cancer Centers, discussed the current treatment paradigm for patients with FL and reviewed the factors he considers when making treatment decisions for this population.

TARGETED ONCOLOGY: What does the current treatment paradigm look like for patients with FL?

Burke: There's a broad spectrum of scenarios with FL, so there are early-stage patients who might have stage I or might just have 1 single lymph node area involved, and those patients will get usually get treated with localized radiation therapy. Then there's a more advanced stage of disease, stage III to IV disease where they're asymptomatic. It may be found, incidentally, with low tumor burden advanced stage. Those patients typically are offered a watch and wait strategy for the patients who don't feel comfortable with that. Single-agent rituximab may be used in that circumstance as well.

The other group of patients is the more advanced stage with high tumor burden. Those are patients who are generally symptomatic from their disease, so for example, they may have fatigue, the lymph nodes may be uncomfortable or threatening or impairing organ function, so it could be blocking off the urine or causing kidney dysfunction, pleural effusions, making them have shorter breath or anemia from bone marrow involvement that's heavy. Those are all patients with high tumor burden disease, and those patients require immediate treatment. They're generally treated, for the most part, with chemoimmunotherapy.

The immunotherapy component is usually either rituximab or obinutuzumab, 1 of 2 different anti-CD20 monoclonal antibodies. The chemotherapy partner is generally 1 of 3 regimens, either CHOP or CVP or bendamustine. Another alternative, although not FDA approved for frontline therapy for those types of patients, is the combination of lenalidomide plus rituximab, which demonstrated in a randomized trial similar efficacy outcomes as chemoimmunotherapy.

TARGETED ONCOLOGY: What are the options in the relapsed/refractory setting?

Burke: Some of that depends on how long ago their prior therapy was and what prior therapy they received. We know that the majority of patients will take many years to relapse, and those patients have an excellent prognosis with a median survival approaching that of patients who don't have FL. The unfortunate patients tend to relapse more quickly. We know that those who relapse within a couple of years of their treatment tend to have a less favorable prognosis, with median survival on the order of 4 to 5 years, so the options for relapsed patients include additional chemoimmunotherapy, maybe the same or may be different from what they received before the combination of lenalidomide and rituximab, and then the PI3K inhibitors, with 3 drugs in that category available for treatment of lymphoma.

Just recently, we had a fourth tool in the arsenal added with tazemetostat, which has a novel mechanism. It's an EZH2 inhibitor, and so that's a new mechanism that we have available to us for relapsed patients. I should also add radioimmunotherapy has been an option for these patients for many years as well and still remains an option for those patients.

TARGETED ONCOLOGY: How do you go about making your treatment selections?

Burke: Risk stratification can be done in a couple of ways. First of all, there's the stage, the low tumor burden versus high tumor burden, the distinction for those with advanced stage, and then there's the risk stratification of scoring systems, such as the flu B score, which has, you know, prognostic implications. There's the FLIPI score and the FLIPI2 score. There's the M7-FLIPI score and the 7-FLIPI score that incorporates results of gene sequencing analysis for us to understand what mutations the cancer cells have. None of these are really perfect, that is they are all somewhat flawed and not perfect in predicting the patient's outcome and clinical course. Most people are not using the M7-FLIPI or doing sequencing of all these genes, so those are ways that 1 can risk stratify FL What was the other part of the question?

TARGETED ONCOLOGY: What factors are important to consider when making treatment decisions?

Burke: If it's a low tumor burden patient, typically we will advocate for a less intensive strategy. if the patient does not want to go with watch and wait, such as single-agent rituximab. For high tumor burden advanced stage, generally most doctors will treat with chemoimmunotherapy, and there's differences among practices in between that rituximab versus obinutuzumab choice, in between the CHOP CVP bendamustine choice. My personal practice has been to be influenced by the GALIUM study, which demonstrated that obinutuzumab appears to be achieving better progression-free survival compared with rituximab when combined with any of those 3 chemotherapy regimens, and so my personal first choice has been obinutuzumab since those data come out.That shoice puts me in the minority.

I think we know that probably more doctors in the country are choosing rituximab over obinutuzumab, and that's okay. That's because there's no known survival advantage to obinutuzumab over rituximab. It does add some toxicity. Some doctors have been using rituximab for much longer and are more comfortable with it, so there's those factors that can leave doctors with good argument to choose rituximab over obinutuzumab.

In terms of the chemotherapy partner, I sit down with a patient and go through what I see to be the pros and cons of the different chemotherapy regimens. I think on the 1 hand CHOP takes about 4 months to get through whereas bendamustine takes about 6 months to get through. They have different side effect profiles with CHOP, so there's more hair loss, more peripheral neuropathy, and a small risk of cardiac toxicity. With bendamustine, we think there's more nausea, more vomiting, less hair loss or no hair loss, but the other comment on bendamustine is that there is suppression of the T cells that is we know the CD4 counts can be suppressed for a long time after bendamustine treatment. That can translate to an increased infection risk that is probably is real. In the galleon study, we saw that there were higher rates of death from infections even after treatment had been finished. Bendamustine, for me, now carries with it the need for some preventative antibiotic. These are complicated discussions, but that's some of the stuff I go through with patients before we make an individual decision as to what they feel is best for them. That's in the initial setting.

For the relapsed patients, a lot of it is about personal preference. What have they done before? Have they been through chemotherapy before, but they don't want to go through chemotherapy again? In my hands, a lot of patients will say I'd rather do kind of a chemotherapy-free type regimen, and so lenalidomide and rituximab is a popular combination in the second-line setting now. PI3 kinase inhibitors are generally reserved for the third or fourth line because of concern about their toxicities, but they can be life saving for patients and really help patients in difficult situations get better and achieve good responses with those 2.

TARGETED ONCOLOGY: Could you elaborate on the approval of tazemetostat for EZH2-positive relapsed/refractory FL?

Burke: Tazemetostat was approved for 2 groups. One group was those who have an EZH2 mutation and have been through 2 prior lines of therapy for FL. The other group was for those who may or may not have an EZH2 mutation but have no suitable or satisfactory alternatives for the treatment of their FK. EZH2 is a gene that is involved in regulating B cells, so it helps to keep B cells in the germinal center. We know that in about 20% of cases of FL, EZH2 can develop gain of function mutations that actually increase the function of EZH2. We know that tazemetostat interferes with those gain of function mutations and decreases the growth of those cells, but it also decreases growth of FL cells even when there is no EZH2 mutation. It can affect both mutated EZH2, and it can affect FL cells when EZH2 is not mutated.

The clinical trial that was developed treated both mutated and unmutated EZH2 patients, and they analyzed them in different cohorts. The mutated patients had a higher overall response rate of 69% with complete responses being about 12%. The unmutated or wild-type EZH2 patients had responses of about half, so it was a 34% overall response rate, and complete remissions were only about 4%. The drug appeared to be more active in the patients who have a mutated EZH2 component of their FL.

The toxicities of the drug were relatively modest. Only 8% of patients had to stop treatment or discontinue therapy due to toxicities, and dose reductions were required in only about 9% of patients. Grade 3 and 4 toxicities were very rare, so very few grade 3/4 toxicities were seen. In terms of the toxicities that were notable, I would say, there was some anemia, some other cytopenias, fatigue, athenea, some upper respiratory tract infections. There was 1 child in a different study who developed T cell lymphoma, and there have been cases of myelodysplastic syndrome and acute myeloid leukemia in the less than 1% range. I'm a little unsure whether this tazemetostat is causing that or whether those are just patients who develop that, for example, from prior chemotherapy exposure, which can certainly cause that as well. It was a well-tolerated treatment. It takes a little bit longer to work than most conventional chemotherapy drugs, so I think the median time to response was almost 4 months. It's not as quite as quick as a chemotherapy regimen in terms of shrinking tumors. Most responses are partial. I think it's a new a new option for patients, and again, a lot of it comes down to patient selection because it has those 2 different indications that it got the label for.

TARGETED ONCOLOGY: What are some of the remaining challenges in the treatment of patients with FL that you think future research efforts should be guided toward going forward?

Burke: I think there's probably 2 big challenges in managing patients with FL. The first is these early relapses, and that is those folks who tend to relapse within 1 to 2 years of finishing their initial treatment. We know they have a much less favorable prognosis, and so it's unclear what the best way is to manage those patients. That is, should they be getting chemotherapy? Should they be getting 1 of these new targeted drugs? Should they be getting autologous or allogeneic stem cell transplant? These are open questions in the field.

We've seen data that some of the targeted drugs can work well, and there's an ongoing SWOG trial that, for doctors who have access to it, I would encourage them to consider. This is a trial for those early relapsing patients with FL where they get randomly assigned to 1 of those 3 different cohorts or treatment arms. One arm is chemotherapy, and it could be the chemotherapy that they didn't receive before either CHOP or bendamustine plus obinutuzumab. The second arm is a lenalidomide-based treatment of lenalidomide plus obinutuzumab. The third arm is a PI3K inhibitor-based treatment. I think they're umbralisib along with obinutuzumab. That demonstrates the equipoise that we have as to exactly what is the best treatment for those early relapses.

The second problem that I think we face in FL, and maybe even a bigger problem, is transformation. Transformation to large cell lymphoma can confer an unfavorable outcome for patients, and it sort of puts them into a whole other disease category of large cell lymphoma. Generally, we will treat those patients with chemotherapy and transplant, but even still, they can certainly have unfavorable outcomes. That's a real problem that we need new and better treatments for FL. There are exciting things in development for FL; just to name a couple, CAR T-cell therapy looks promising and effective in FL, but that certainly has not insignificant toxicities. Bispecific antibodies appear to be having good activity against FL in clinical trials, and I know that additional development is ongoing with those. There's some exciting new molecules and drugs being developed to improve outcomes even better.